The present invention relates to novel vanilloid receptor ligands, to processes for the production thereof, to medicinal drugs containing said compounds and to the use of said compounds for the production of medicinal drugs.
The treatment of pain, particularly neuropathic pain, is of great significance in the medical field. There is a global need for effective pain therapies. The urgent need for action to provide a patient-friendly und targeted treatment of chronic and non-chronic states of pain, this being taken to mean the successful und satisfactory treatment of pain for patients, is documented by the large number of scientific papers which have recently appeared in the field of applied analgesics or in basic research concerning nociception.
A suitable starting point for the treatment of pain; particularly of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain and more preferably neuropathic pain; is the vanilloid receptor of subtype 1 (VR1/TRPV1), frequently also designated as the capsaicin receptor. This receptor is stimulated, inter alia, by vanilloids such as capsaicin, heat, and protons and plays a central part in the generation of pain. Furthermore, it is significant for a large number of other physiological and pathophysiological processes such as migraine; states of depression; neurodegenerative disorders; cognitive disorders; anxiety; epilepsy; coughing; diarrhea; pruritus; inflammations; disorders of the cardiovascular system; food intake disorders; medicine addiction; medicine abuse and, in particular, urinary incontinence.
It is thus an object of the invention to provide novel compounds which are particularly suitable for use as pharmacologically active substances in medicinal drugs, preferably in medicinal drugs for treatment of disorders or diseases that are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 receptors). It has now been found, surprisingly, that the substituted compounds of the general formula I stated below show excellent affinity to the vanilloid receptor of subtype 1 (VR1/TRPV1 receptor) and are therefore particularly suitable for the prophylaxis and/or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1). The substituted compounds corresponding to the following formula I also show anti-inflammatory activity.
It is thus at object of the present invention to provide substituted compounds of the general formula I,
in which    n stands for 0, 1, 2, 3, or 4;    R1 stands for H; F; Cl; Br; I; —SF5; —NO2; —CN; —NH2; —OH; —SH; —C(═O)—NH2; —S(═O)2—NH2; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)2—OH; —C(═NH)—NH2; —C(═NH)—NH—R9; —N═C(NH2)2; —N═C(NHR10)—(NHR11); —O—P(═O)2—O—R12; —NHR13; —NR14R15; —NH—C(═O)—R13; —OR16; —SR17; —C(═O)—NHR18; —C(═O)—NR19R20; —S(═O)2—NHR21; —S(═O)2—NR22R23; —C(═O)—OR24; —C(═O)—R25; —S(═O)—R26; or —S(═O)2—R27 or for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    R2 stands for H; F; Cl; Br; I; —SF5; —NO2; —CN; —NH2; —OH; —SH; —C(═O)—NH2; —S(═O)2—NH2; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)2—OH; —C(═NH)—NH2; —C(═NH)—NH—R9; —N═C(NH2)2; —N═C(NHR10)—(NHR11); —O—P(═O)2—O—R12; —NHR13; —NR14R15; —NH—C(═O)—R13; —OR16; —SR17; —C(═O)—NHR18; —C(═O)—NR19R20; —S(═O)2—NHR21; —S(═O)2—NR22R23; —C(═O)—OR24; —C(═O)—R25; —S(═O)—R26; or —S(═O)2—R27 or for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    R3 stands for H; F; Cl; Br; I; —SF5; —NO2; —CN; —NH2; —OH; —SH; —C(═O)—NH2; —S(═O)2—NH2; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)2—OH; —C(═NH)—NH2; —C(═NH)—NH—R9; —N═C(NH2)2; —N═C(NHR10)—(NHR11); —O—P(═O)2—O—R12; —NHR13; —NR14R15; —NH—C(═O)—R13; —OR16; —SR17; —C(═O)—NHR18; —C(═O)—NR19R20; —S(═O)2—NHR21; —S(═O)2—NR22R23; —C(═O)—OR24; —C(═O)—R25; —S(═O)—R26; or —S(═O)2—R27 or for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    R4 stands for H; F; Cl; Br; I; —SF5; —NO2; —CN; —NH2; —OH; —SH; —C(═O)—NH2; —S(═O)2—NH2; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)2—OH; —C(═NH)—NH2; —C(═NH)—NH—R9; —N═C(NH2)2; —N═C(NHR10)—(NHR11); —O—P(═O)2—O—R12; —NHR13; —NR14R15; —NH—C(═O)—R13; —OR16; —SR17; —C(═O)—NHR18; —C(═O)—NR19R20; —S(═O)2—NHR21; —S(═O)2—NR22R23; —C(═O)—OR24; —C(═O)—R25; —S(═O)—R26; or —S(═O)2—R27 or for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    R5 stands for H; F; Cl; Br; I; —SF5; —NO2; —CN; —NH2; —OH; —SH; —C(═O)—NH2; —S(═O)2—NH2; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)2—OH; —C(═NH)—NH2; —C(═NH)—NH—R9; —N═C(NH2)2; —N═C(NHR10)—(NHR11); —O—P(═O)2—O—R12; —NHR13; —NR14R15; —NH—C(═O)—R13; —OR16; —SR17; —C(═O)—NHR18; —C(═O)—NR19R20; —S(═O)2—NHR21; —S(═O)2—NR22R23; —C(═O)—OR24; —C(═O)—R25; —S(═O)—R26; or —S(═O)2—R27 or for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    R6 stands in each case for hydrogen or for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    R7 stands for hydrogen or —OH;or    R6 and R7 form, together with the interconnecting carbon atom as ring member, a saturated or unsaturated, unsubstituted or at least monosubstituted three-membered, four-membered, five-membered, or six-membered cycloaliphatic radical;    R8 stands for —SF5; —O—CF3; —CF3; —O—CFH2; —O—CF2 H; —CFH2; —CF2 H; or for an unsubstituted or at least monosubstituted tert-butyl radical;    T stands for C—R35 and U stands for C—R36 and V stands for N and W stands for C—R38; or    T stands for C—R35 and U stands for N and V stands for C—R37 and W stands for C—R38; or    T stands for N and U stands for C—R36 and V stands for C—R37 and W stands for C—R38; or    T stands for N and U stands for N and V stands for C—R37 and W stands for C—R38; or    T stands for N and U stands for C—R36 and V stands for N and W stands for C—R38; or    T stands for C—R35 and U stands for N and V stands for N and W stands for C—R38; or    T stands for C—R35 and U stands for C—R36 and V stands for C—R37 and W stands for C—R38;    R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and    R27 each independently            stand for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;        for an unsaturated or saturated, unsubstituted or at least monosubstituted, three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic radical optionally containing at least one heteroatom as ring member, which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or two to six-membered heteroalkylene group;        or for an unsubstituted or at least monosubstituted five-membered to fourteen-membered aryl radical or heteroaryl radical, which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or two to six-membered heteroalkylene group;            R35, R36, and R37 each independently            stand for H; F; Cl; Br; I; —SFS; —NO2; —CF3; and —CN; —NH2; —OH; —SH; —C(═O)—NH2; —S(═O)2—NH2; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; and —S(═O)2—OH; —NHR13; —NR14R15; —NH—C(═O)—R13; —OR16, —SR17; —C(═O)—NHR18; —C(═O)—NR19R20; —S(═O)2—NHR21; and —S(═O)2—NR22R23; —C(═O)—OR24; —C(═O)—R25; —S(═O)—R26; —S(═O)2R27         for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;        or for an unsubstituted or at least monosubstituted five-membered to fourteen-membered aryl radical or heteroaryl radical, which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6-alkynylene group;            R38 stands for F; Cl; Br; I; —SF5; —NO2; —CF3; —CF2Cl; —CN; —NH2; —OH; —SH; —C(═NH2; —S(═O)2—NH2; —C(═O)—NH—OH; and —C(═O)—OH; —C(═O)—H; —S(═O)2—OH; —NHR39; —NR40R41; —OR42; —SR43; —C(═O)—NHR44; —C(═O)—NR45R46; and —S(═O)2—NHR47; —S(═O)2—NR48R49; —C(═O)—OR50; —C(═O)—R51; —S(═O)—R52; —S(═O)2—R53; —C(═NH)—NH2; —C(═NH)—NH—R54; —N═C(NH2)2; and —N═C(NHR55)—(NHR56);            for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;        for an unsaturated or saturated, unsubstituted or at least monosubstituted three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic radical optionally exhibiting at least one heteroatom as ring member, each of which is bonded to the parent structure over a carbon atom in the ring of the cycloaliphatic radical and is condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group;        or for an unsubstituted or at least monosubstituted five-membered to fourteen-membered aryl radical or heteroaryl radical, which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6-alkynylene group;            R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56 each independently            stand for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;        for an unsaturated or saturated, unsubstituted or at least monosubstituted, three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic radical optionally containing at least one heteroatom as ring member, which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or two to six-membered heteroalkylene group;        or for an unsubstituted or at least monosubstituted five-membered to fourteen-membered aryl radical or heteroaryl radical, which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or two to six-membered heteroalkylene group;or            R40 and R41 form, together with the interconnecting nitrogen atom as ring member, a saturated or unsaturated four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered heterocycloaliphatic radical, which is unsubstituted or substituted by 1, 2, 3, 4, or 5 radicals R57 and optionally exhibits at least one further heteroatom as ring member, and which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system;    R57 stands for —NHR58, —NR59R60, or for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    R58, R59, and R60 each independently            stand for —C(═O)—R61;        for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical        or for an unsubstituted or at least monosubstituted five-membered to fourteen-membered aryl radical or heteroaryl radical, which can be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system and/or can be bonded via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group;and            R61 stands for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 radical;    each optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers thereof, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or each in the form of corresponding salts, or each in the form of corresponding solvates;wherein    the aforementioned aliphatic C1-10 radicals and tert-butyl radicals can each be optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), —N(C1-5 alkyl)-(C1-5 alkyl), —C(═O)—O—(C1-5 alkyl), —O—C(═O)—(C1-5 alkyl), —O-phenyl, phenyl, —OCF3, and —SCF3;    the aforementioned two to six-membered heteroalkylene groups, C1-6 alkylene groups, and C2-6 alkenylene groups and C2-6 alkynylene groups can each be optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), —N(C1-5 alkyl)-(C1-5 alkyl), —OCF3, and —SCF3;    the aforementioned heteroalkylene groups each optionally exhibit 1, 2, or 3 heteroatom(s) independently selected from the group consisting of oxygen, sulfur, and nitrogen (NH) as link(s);    the aforementioned (hetero)cycloaliphatic radicals are optionally each substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —(C1-6 alkylene)-OH, ═CH2, —O—(C1-5 alkylene)oxetanyl, —(C1-5 alkylene)-O—(C1-5 alkylene)oxetanyl, —CH2—NH—(C1-5 alkyl), —CH2—N(C1-5 alkyl)2, —N[C(═O)—(C1-5 alkyl)]phenyl, —CH2—O—(C1-5 alkyl), oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—(C1-5 alkyl), —O—C(═O)—(C1-5 alkyl), —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—(C1-5 alkyl), —(C1-5 alkyl), —C(═O)—(C1-5 alkyl), —C(═O)—OH, —C(═O)—O—(C1-5 alkyl), —NH—(C1-5 alkyl), —N(C1-5 alkyl)2, —NH-phenyl, —N(C1-5 alkyl)phenyl, cyclohexyl, cyclopentyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, piperidinyl, pyrrolidinyl, —(CH2)pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic moiety of the radicals oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, —N[C(═O)—(C1-5 alkyl)]phenyl, —NH-phenyl, —N(C1-5 alkyl)phenyl, —(CH2)pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —(C1-5 alkyl, —O—(C1-5 alkyl), —O—CF3, —S—CF3, phenyl, and —O-benzyl,and, unless otherwise stated, the aforementioned (hetero)cycloaliphatic radicals can each optionally exhibit 1, 2, or 3 (further) heteroatom(s) independently selected from the group consisting of oxygen, nitrogen, and sulfur;    the rings of the aforementioned monocyclic or polycyclic ring systems can each be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—(C1-5 alkyl), —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—(C1-5 alkyl), —(C1-5 alkyl), —C(═O)—(C1-5 alkyl), —C(═O)—OH, —C(═O)—O—(C1-5 alkyl), —NH—(C1-5 alkyl), —N(C1-5 alkyl)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —(C1-5 alkyl), —O—(C1-5 alkyl), —O—CF3, —S—CF3, phenyl, and —O-benzyl,    and the rings of the aforementioned monocyclic or polycyclic ring systems are each five-membered, six-membered, or seven-membered and can each optionally exhibit 1, 2, 3, 4, or 5 heteroatom(s) as ring member(s), which are independently selected from the group consisting of oxygen, nitrogen, and sulfur;    and the aforementioned aryl radicals or heteroaryl radicals can each be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—(C1-5 alkyl), —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—(C1-5 alkyl), —(C1-5 alkyl), —C(═O)—OH, —C(═O)—O—(C1-5 alkyl), —NH—(C1-5 alkyl), —N(C1-5 alkyl)2, —NH—S(═O)2—(C1-5 alkyl), —NH—C(═O)—O—(C1-5 alkyl), —C(═O)—H, —C(═O)—(C1-5 alkyl), —C(═O)—NH2, —C(═O)—NH—(C1-5 alkyl), —C(═O)—N—(C1-5 alkyl)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —(C1-5 alkyl), —O—(C1-5 alkyl), —O—CF3, —S—CF3, phenyl, and —O-benzyl, and    the aforementioned heteroaryl radicals can each optionally exhibit 1, 2, 3, 4, or 5 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen, and sulfur as ring member(s).
The term “heteroalkylene” designates an alkylene chain in which one or more carbons have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH). Heteroalkylene groups can preferably contain 1, 2, or 3 heteroatom(s) and more preferably one heteroatom, independently selected from the group consisting of oxygen, sulfur and nitrogen (NH), as link(s). Heteroalkylene groups can preferably be two to six-membered and more preferably two or three-membered.
Examples of heteroalkylene groups include —CH2—CH2—O—CH2—, —CH2—CH(CH3)—O—CH2—, —(CH2)—O—, —(CH2)2—O—, —(CH2)3—O—, —(CH2)4—O—, —O—(CH2)—, —O—(CH2)2—, —O—CH2)3—, —O—(CH2)4—, —C(C2H5)—(H)—O—, —O—C(C2H5)—(H)—, —CH2—O—CH2—, —CH2—S—CH2—, —CH2—NH—CH2—, —CH2—NH—, and —CH2—CH2—NH—CH2—CH2.
If one or more of the aforementioned substituents exhibit a linear or branched C1-6 alkylene group, these can be preferably selected from the group consisting of —(CH2)—, —(CH2)2—, —C(H)—(CH3)—, —(CH2)3—, —(CH2)4—, —(CH2)5—, —C(H)—(C(H)—(CH3)2)—, and —C(C2H5)—(H)—.
Saturated or unsaturated C1-10 aliphatic radicals can stand for a C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl radical. C2-10 alkenyl radicals have at least one and preferably 1, 2, 3, or 4 C—C double bonds and C2-10 alkynyl radicals at least one and preferably 1, 2, 3, or 4 C—C triple bonds.
Preference is given to C1-10 alkyl radicals selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbut-1-yl, 2-pentyl, 3-pentyl, sec-pentyl, neopentyl, 4-methylpent-1-yl, (3,3)-dimethylbut-1-yl, n-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, and (2,6)-dimethylhept-4-yl, which can be optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of —O-phenyl, —O—C(═O)—CH3, —O—C(═O)—C2H5, —O—C(═O)—CH(CH3)2, —O—C(═O)—C(CH3)3, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—CH(CH3)2, —C(═O)—O—C(CH3)3, F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —S—CH3, —S—C2H5, —S—CH(CH3)2, —S—C(CH3)3, —NH—CH3, —NH—C2H5, —NH—C(CH3)3, —N(CH3)2, —N(C2H5)2, —N(CH3)—(C2H5), —OCF3, and —SCF3.
In another preferred embodiment, C2-10 alkenyl radicals are selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropen-1-yl, 3-methylbut-2-en-1-yl, (3,3)-dimethylbut-1-enyl, 2-methylbuten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 1-heptenyl, and 1-octenyl, which can be optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —S—CH3, —S—C2H5, —S—CH(CH3)2, —S—C(CH3)3, —NH—CH3, —NH—C2H5, —NH—C(CH3)3, —N(CH3)2, —N(C2H5)2, —N(CH3)—(C2H5), —OCF3, and —SCF3.
Preference is also given to C2-10 alkynyl radicals selected from the group consisting of (3,3)-dimethylbut-1-ynyl, 4-methylpent-1-ynyl, 1-hexynyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl, which can be optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —S—CH3, —S—C2H5, —S—CH(CH3)2, —S—C(CH3)3, —NH—CH3, —NH—C2H5, —NH—C(CH3)3, —N(CH3)2, —N(C2H5)2, —N(CH3)—(C2H5), —OCF3, and —SCF3.
Particularly preferred optionally substituted C1-10 aliphatic radicals are selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, —CCl2F, —CBr3, —CH2—CN, —CH2—O—CH3, —CH2—O—CF3, —CH2—SF3, —CH2—NH2, —CH2—OH, —CH2—SH, —CH2—NH—CH3, —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—N(CH3)—(C2H5), ethyl, —CF2—CH3, —CHF—CF2Cl, —CF2—CFCl2, —CH2—CH2—NH2, —CH2—CH2—OH, —CH2—CH2—SH, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)2, —CH2—CH2—N(C2H5)2, —CH2—CH2—N(CH3)—(C2H5), —CH2—CF3, —C2F5, —CH2—CCl3, —CH2—CBr3, —CH2—CH2—CN, n-propyl, —CH2—CH2—CH2—OH, —CH2—CH2—CH2—SH, —CH2—CH2—CH2—NH2, —CH2—CH2—CH2—NH—CH3, —CH2—CH2—CH2—N(CH3)2, —CH2—CH2—CH2—N(C2H5)2, —CH2—CH2—CH2—N(CH3)—(C2H5), —CH2—CH2—O—CH3, —CF2—CF2—CF3, —CF(CF3)2, isopropyl, —CH2—CH2—CH2—CN, —CH2—O—CH2—CH3, —CH2—CH2—SF3, —CH2—CH2—OCF3, —CH(CH3)—(O—CH3), —CH(CH3)—(S—CH3), n-butyl, —CF2—CF2—CF2—CF3, —CH2—CH2—CH2—CH2—CN, —CH2—CH2—CH2—CF3, —CH2—CH2—CH2—CH2—CF3, —CH2—O—C(═O)—CH3, —CH2—O—C(═O)—C2H5, —CH2—O—C(═O)—CH(CH3)2, —CH2—O—C(═O)—C(CH3)3, —CH2—C(═O)—O—CH3, —CH2—C(═O)—O—C2H5, —CH2—C(═O)—O—C(CH3)3, —CH2—CH2—O—CH3, —CH2—CH2—O—C2H5, —CH2—CH2—O-phenyl, —CH2—CH2—CH2—O—CH3, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbutene-2-yl, (1,1,2)-trifluoro-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, —CF═CF2, —CCl═CCl2, —CH2—CF═CF2, —CH2—CCl═CCl2, —C≡C—I, —C≡C—, and —C≡C—Cl.
If one or more of the aforementioned substituents stand for a (hetero)cycloaliphatic radical, which can be optionally condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted monocyclic or polycyclic ring system, this can preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, (1,2,3,6)-tetrahydropyridinyl, azepanyl, azocanyl, diazepanyl, dithiolanyl, (1,3,4,5)-tetrahydropyrido[4.3-b]indolyl, (3,4)-dihydro-1H-isoquinolinyl, (1,3,4,9)-tetrahydro[b]carbolinyl, and (1,3)-thiazolidinyl.
As examples of suitable (hetero)cycloaliphatic radicals, which can be unsubstituted or monosubstituted or polysubstituted and are condensed with a monocyclic or bicyclic ring system, there may be mentioned (4,5,6,7)-tetrahydroisoxazolo[5.4-c]pyridinyl, (2,3)-dihydro-1H-indenyl, 3-azabicyclo[3.1.1]heptyl, 3-acabicyclo[3.2.1]octyl, 6-azabicyclo[3.3.1]heptyl, 8-acabicyclo[3.2.1]octyl, isoindolyl, indolyl, (1,2,3,4)-tetrahydroquinolinyl, (1,2,3,4)-tetrahydroisoquinolinyl, (2,3)-dihydro-1H-isoindolyl, (1,2,3,4)-tetrahydronaphthyl, (2,3)-dihydrobenzo[1.4]dioxinyl, benzo[1.3]dioxolyl, (1,4)-benzodioxanyl, (2,3)-dihydrothieno[3.4-b][1.4]dioxinyl, (3,4)-dihydro-2H-benzo[1.4]oxazinyl, octahydro-1H-isoindolyl, and octahydropyrrolo[3.4-c]pyrrolyl.
(Hetero)cycloaliphatic radicals can form, within the scope of the present invention, a spirocyclic radical with another (hetero)cycloaliphatic radical via a carbon atom common to both rings.
Examples of suitable spirocyclic radicals include a 6-azaspiro[2.5]octyl radical, an 8-azaspiro[4.5]decyl radical and a 1-oxa-2,8-diazaspiro[4.5]dec-2-enyl radical. More preferably the (hetero)cycloaliphatic radicals can each be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—CH3, —S—C2H5, —S—CH(CH3)2, —S—C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—CH(CH3)2, —C(═O)—C(CH3)3, —C(═O)—OH, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—CH(CH3)2, —C(═O)—O—C(CH3)3, —NH—CH3, —NH—C2H5, —NH—C(CH3)3, —N(CH3)2, —N(C2H5)2, —N(CH3)—(C2H5), —CH2—OH, —CH2—CH2—OH, ═CH2, —CH2—O—CH2-oxetanyl, —O—CH2-oxetanyl, —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—NH—CH3, —CH2—NH—C2H5, —N—[C(═O)—C2H5]-phenyl, —N—[C(═O)—CH3]-phenyl, —CH2—O—CH3, —CH2—O—CH2—CH3, —NH-phenyl, —N(CH3)phenyl, —N(C2H5)phenyl, —N(C2H5)phenyl, —O—CH2—CH2—CH2—CH3, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, cyclohexyl, cyclopentyl, piperidinyl, pyrrolidinyl, —O—C(═O)—CH3, —O—C(═O)—C2H5, —O—C(═O)—C(CH3)3, —(CH2)pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic moiety of the radicals oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, —N—[C(═O)—C2H5]phenyl, —N—[C(═O)—CH3]phenyl, —NH-phenyl, —N(CH3)phenyl, —N(C2H5)phenyl, —(CH2)pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
If one or more of the aforementioned substituents stand for an aryl radical, this can preferably be selected from the group consisting of phenyl and naphthyl (1-naphthyl and 2-naphthyl).
If one or more of the aforementioned substituents stand for a heteroaryl radical, this can preferably be selected from the group consisting of tetraazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, benzoxazolyl, benzisoxazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl.
Examples of suitable aryl and heteroaryl radicals, which may be unsubstituted or monosubstituted or polysubstituted and are condensed with a monocyclic or bicyclic ring system, include isoindolyl, indolyl, (1,2,3,4)-tetrahydroquinolinyl, (1,2,3,4)-tetrahydroisoquinolinyl, (2,3)-dihydro-1H-isoindolyl, (1,2,3,4)-tetrahydronaphthyl, (2,3)-dihydrobenzo[1.4]dioxinyl, (2,3)-dihydrothieno[3.4-b][1.4]dioxinyl, benzo[1.3]dioxolyl, and (1,4)-benzodioxanyl.
More preferably, the aryl radicals or heteroaryl radicals can each be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—CH3, —S—C2H5, —S—CH(CH3)2, —S—C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—OH, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—CH(CH3)2, —C(═O)—O—C(CH3)3, —NH—CH3, —NH—C2H5, —NH—C(CH3)3, —N(CH3)2, —N(C2H5)2, —N(CH3)—(C2H5), —NH—S(═O)2—CH3, —NH—S(═O2)—C2H5, —NH—S(═O)2—CH(CH3)2, —NH—C(═O)—O—CH3, —NH—C(═O)—O—C2H5, —NH—C(═O)—O—C(CH3)3, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—CH(CH3)2, —C(═O)—C(CH3)3, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—NH—C2H5, —C(═O)—N(CH3)2, —C(═O)—N(C2H5)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
If a polycyclic ring system such as a bicyclic ring system is present, the different rings can independently exhibit a different degree of saturation, i.e. be saturated or unsaturated. A polycyclic ring system is preferably a bicyclic ring system.
Examples of aryl radicals condensed with a monocyclic or polycyclic ring system include (1,3)-benzodioxolyl and (1,4)-benzodioxanyl.
If one or more of the aforementioned substituents have a monocyclic or polycyclic ring system, this can preferably be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—CH3, —S—C2H5, —S—CH(CH3)2, —S—C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—OH, —C(═O)—O—CH3, —C(═O)—O—C2H5, —C(═O)—O—CH(CH3)2, —C(═O)—O—C(CH3)3, —NH—CH3, —NH—C2H5, —NH—C(CH3)3, —N(CH3)2, —N(C2H5)2, —N(CH3)—(C2H5), —NH—C(═O)—O—CH3, —NH—C(═O)—O—C2H5, —NH—C(═O)—O—C(CH3)3, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—CH(CH3)2, —C(═O)—C(CH3)3, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)-nH-C2H5, —C(═O)—N(CH3)2, —C(═O)—N(C2H5)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
If R41 and R42 together with the interconnecting nitrogen atom as ring member form a heterocycloaliphatic radical, which is substituted by 1, 2, 3, 4, or 5 radicals R57, said radicals R57 may each be independently from one another selected from the above given meanings.
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R2 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R3 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R4 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R5 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27, each independently            stand for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, —CF2—CH3, —CH2—CF3, —C2F5, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl and ethenyl;            R42 stands for a radical selected from the group consisting of methyl, —CH2—O—CH3, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3)-dimethylbutyl, —CH2—CH2—O—CH3, —CH2—CH2—O—C2H5, and —CH2—CH2—CH2—O—CH3,            or for a radical selected from the group consisting of 2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which can be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Special preference is given to compounds of the general formula Ia,
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27,    R2 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R3 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R4 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R5 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently            stand for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and ethenyl;            R42 stands for a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;            or for a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which can be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Very special preference is given to compounds of the general formula Ia,
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br or I;    R2 stands for H; F; Cl; Br; I; methyl; —OH; —NH2 or —OR16;    R3 stands for H; F; Cl; Br; I; —NO2; —OH; —NH2; —NH—C(═O)—R13, —OR16; SR17; —S(═O)—NR22R23 or —S(═O)—R27;    R4 stands for H; F; Cl; Br; I; methyl, —OH; —NH2 or —OR16;    R5 stands for H; F; Cl; Br; or I;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently            stand for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and ethenyl;            R42 stands for a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;            or for a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which can be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preference is given to compounds of the general formula Ib,
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R2 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R3 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R4 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R5 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently            stand for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, —CF2—CH3, —CH2—CF3, —C2F5, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl and ethenyl;            R43 stands for a radical selected from the group consisting of methyl, —CH2—O—CH3, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3)-dimethylbutyl, —CH2—CH2—O—CH3, —CH2—CH2—O—C2H5, and —CH2—CH2—CH2—O—CH3;            or for a radical selected from the group consisting of 2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which can be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Special preference is given to compounds of the general formula Ib,
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27,    R2 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R3 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R4 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R5 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently            stand for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and ethenyl;            R43 stands for a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;            or for a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which can be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Very special preference is given to compounds of the general formula Ib,
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br or I;    R2 stands for H; F; Cl; Br; I; methyl; —OH; —NH2 or —OR16;    R3 stands for H; F; Cl; Br; I; —NO2; —OH; —NH2; —NH—C(═O)—R13, —OR16; SR17; —S(═O)—NR22R23 or —S(═O)—R27;    R4 stands for H; F; Cl; Br; I; methyl, —OH; —NH2 or —OR16;    R5 stands for H; F; Cl; Br; or I;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently            stand for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and ethenyl;            R43 stands for a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;            or for a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which can be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preference is given to compounds of the general formula Ic,
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R2 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R3 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R4 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R5 stands for H; F; Cl; Br; I; —NO2; —CF3; —CN; —NH2; —OH; —NH—C(═O)—R13; —OR16; —SR17; —S(═O)2—NR22R23; —S(═O)2—R27, or for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently            stand for a radical selected from the group consisting of methyl, —CF3, —CHF2, —CH2F, ethyl, —CF2—CH3, —CH2—CF3, —C2F5, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl, and ethenyl;            R40 and R41 each independently            stand for a radical selected from the group consisting of methyl, —CH2—O—CH3, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3)-dimethylbutyl, —CH2—CH2—O—CH3, —CH2—CH2—O—C2H5, and —CH2—CH2—CH2—O—CH3;        or for a radical selected from the group consisting of 2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which can be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;or            R40 and R41 form, together with the interconnecting nitrogen atom as ring member, a radical selected from the group consisting of 3-azabicyclo[3.1.1]heptyl, 6-azaspiro[2.5]octyl, 3-acabicyclo[3.2.1]octyl, 6-azabicyclo[3.3.1]heptyl, 8-acabicyclo[3.2.1]octyl, 1-oxa-2,8-diazaspiro[4.5]dec-2-enyl, azocanyl, isoindolyl, indolyl, (1,2,3,6)-tetrahydropyridinyl, (4,5,6,7)-tetrahydroisoxazolo[5.4-c]pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl, and thiomorpholinyl, of which the heterocycloaliphatic moiety can in each case be unsubstituted or substituted by 1, 2, 3, 4, or 5 radicals R57;    R57 stands for —NHR58, —NR69R60, or for an alkyl radical selected from the group consisting of —CF3, —CH2—CF3, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;    R58, R59, and R69 each independently            stand for —C(═O)—R61;        for an alkyl radical selected from the group consisting of —CF3, —CH2—CF3, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or for a radical selected from the group consisting of phenyl and naphthyl, and each radical can be bonded via a —(CH2)—, —(CH2)2— or —(CH2)3 group and/or can each be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —O—CH3, —O—C2H5, —O—CH(CH3)2, —O—C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;and            R61 stands for an alkyl radical selected from the group consisting of —CF3, —CH2—CF3, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Special preference is given to compounds of the general formula Ic,
in which    D stands for N or CH;    R1 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27,    R2 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R3 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R4 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —SR17, —S(═O)2—NR22R23 or —(S═O)—R27;    R5 stands for H; F; Cl; Br; I; methyl, ethyl, —NO2; —OH; —NH2; —NH—C(═O)—R13; —OR16; —S(═O)2—NR22R23 or —(S═O)—R27;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently            stand for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and ethenyl;            R40 and R41 form, together with the interconnecting nitrogen atom as ring member, a radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepanyl, of which the heterocycloaliphatic moiety can in each case be unsubstituted or substituted by 1, 2, 3, 4, or 5 radicals R57;and    R57 stands for an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Very special preference is given to compounds of the general formula Ic,
in which    D stands for N or CH; R1 stands for H; F; Cl; Br; or I;    R1 stands for H; F; Cl; Br or I;    R2 stands for H; F; Cl; Br; I; methyl; —OH; —NH2 or —OR16;    R3 stands for H; F; Cl; Br; I; —NO2; —OH; —NH2; —NH—C(═O)—R13, —OR16; SR17; —S(═O)—NR22R23 or —S(═O)—R27;    R4 stands for H; F; Cl; Br; I; methyl, —OH; —NH2 or —OR16;    R5 stands for H; F; Cl; Br; or I;    R8 stands for —SF5; —O—CF3; —CF3; tert-butyl; or —C(CH3)2(CH2OH);    R13, R16, R17, R22, R23 and R27 each independently stand for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and ethenyl;    R40 and R41 form, together with the interconnecting nitrogen atom as ring member, a radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepanyl, of which the heterocycloaliphatic moiety can in each case be unsubstituted or substituted by 1, 2, 3, 4, or 5 radicals R57;and    R57 stands for an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Even more preference is given to compounds of the general formulas I, Ia, Ib, and Ic selected from the group consisting of    [1] 2-(4-Amino-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [2] 2-(3,5-Dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [3] 2-(4-Amino-3-bromo-5-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [4] 2-(3-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [5] 2-(2,4-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [6] 2-(2,6-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-)methyl)acetamide;    [7] 2-(2,5-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [8] 2-(4-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [9] 2-(4-Hydroxy-3-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [10] 2-(3,5-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [11] 2-(3,4-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [12] 2-(4-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [13] 2-(3-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [14] 2-(3,4-Diaminophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [15] N-(2-Butoxy-6-tert-butylpyridin-3-ylmethyl)-2-(3,4-diamino-phenyl)-propionamide;    [16] N-((6-tert-Butyl-2-(4-methylpiperidin-1-yl)pyridin-3-yl)methyl)-2-(3,4-diaminophenyl)propanamide;    [17] N-((6-tert-Butyl-2-(cyclohexylthio)pyridin-3-yl)methyl)-2-(3,4-diaminophenyl)propanamide;    [18] 2-(4-Acetamido-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [19] 2-(3,5-Dibromo-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [20] 2-(4-Amino-3,5-dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    [21] 2-(3-Brom-4-hydroxy-5-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [22] 2-(4-Amino-3,5-dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [23] 2-(3,5-Dibromo-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;    [24] 2-(3-Amino-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide; and    [25] 2-(3,5-Dibromophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide;    [26] 2-(4-Amino-3,5-difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [27] 2-(3-Fluoro-5-hydroxy-4-nitrophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [28] 2-(3-Chloro-4-(methylthio)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [29] 2-(3-Chloro-4-(methylsulfonyl)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [30] 2-(3-Fluoro-4-(methylthio)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [31] 2-(3-Fluoro-4-(methylsulfonyl)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [32] 2-(4-(N,N-Dimethylsulfamoyl)-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [33] N-(2-Fluoro-4-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)phenyl)acrylamide,    [34] N-(2-Fluoro-6-iodo-4-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)phenyl)acrylamide,    [35] 2-(4-Methoxy-3,5-dimethylphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [36] 2-(3,5-Difluoro-4-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [37] 2-(4-Hydroxy-3,5-dimethylphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    [38] 2-(3,5-Difluoro-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,each optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers thereof, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or each in the form of corresponding salts, or each in the form of corresponding solvates;
Furthermore, preference may be given to compounds of the invention of the general formulas I, Ia, Ib and Ic, which in the FLIPR assay using CHO—K1 cells, which have been transfected with the human VR1 gene in a concentration below 2000 nM, preferably below 1000 nM, more preferably below 300 nM, even more preferably below 100 nM, still more preferably below 75 nM, very preferably below 50 nM and most preferably below 10 nM, cause a 50 percent displacement of capsaicin present in a concentration of 100 nM. In the FLIPR assay, the Ca2+ influx is quantified with the aid of a Ca2+-sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA), as described below.
The invention further relates to a process for the production of compounds of the above general formula I, according to which at least one compound of the general formula II,
in which    R8, U, T, V, and W have the aforementioned meanings, m stands for 0, 1, 2, or 3, and R stands for hydrogen or for a linear or branched C1-6 alkyl radical, in a reaction medium, in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, sodium, potassium hydride, lithium aluminum hydride, sodium tetrahydridoborate, and di(isobutyl)aluminum hydrideis converted to at least one compound of the general formula III,
in which    R8, U, T, V, and W have the meanings stated above and m stands for 0, 1, 2, or 3, and this is optionally purified and/or isolated,    and at least one compound of the general formula III is converted, in a reaction medium in the presence of diphenylphosphorylazide or in the presence of HN3, to at least one compound of the general formula IV,
in which    R8, U, T, V, and W have the meanings stated above and m stands for 0, 1, 2, or 3, and this is optionally purified and/or isolated,    and at least one compound of the general formula IV is converted, in a reaction medium in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, potassium hydride, lithium aluminum hydride, sodium tetrahydridoborate, and di(isobutyl)aluminum hydride,    or in a reaction medium in the presence of a catalyst, preferably in the presence of a catalyst based on platinum or palladium, more preferably in the presence of palladium-on-charcoal, and in the presence of hydrogen or in the presence of hydrazine,    or in a reaction medium in the presence of triphenylphosphine to at least one compound of the general formula V,
in which    R8, U, T, V, and W have the meanings stated above and m stands for 0, 1, 2, or 3, and this is optionally purified and/or isolated,    or at least one compound of the general formula VI
in which    R8, U, T, V, and W have the meanings stated above and m stands for 0, 1, 2, or 3, in a reaction medium is converted, in the presence of at least one catalyst, preferably in the presence of at least one catalyst based on palladium or platinum, more preferably in the presence of palladium-on-charcoal, under a blanket of hydrogen, optionally in the presence of at least one acid, preferably in the presence of hydrochloric acid, or in the presence of at least one reducing agent selected from the group consisting of BH3 bullet S(CH3)2, lithium aluminum hydride, and sodium tetrahydridoborate, optionally in the presence of NiCl2,    to form at least one compound of the general formula V, optionally in the form of a corresponding salt, preferably in the form of a corresponding hydrochloride, and this is optionally purified and/or isolated,    and at least one compound of the general formula V is caused to react with at least one compound of the general formula VII,
in which    R1, R2, R3, R4, R5, R6, and R7 have the meanings stated above, in a reaction medium, optionally in the presence of at least one suitable coupling agent, optionally in the presence of at least one base,    or with at least one compound of the general formula VIII,
in which    R1, R2, R3, R4, R5, R6, and R7 have the meanings stated above and LG stands for a leaving group, preferably for a chlorine radical or bromine atom, in a reaction medium, optionally in the presence of at least one base, to form at least one compound of the general formula I,
in which
T, U, V, W, R1, R2, R3, R4, R5, R6, R7, and R8, have the meanings stated above and n stands for 1, 2, 3, or 4, and this is optionally purified and/or isolated.
The invention further relates to a process for the production of compounds of the above general formula I, according to which at least one compound of the general formula X,
in which    R8, U, T, V, and W have the meanings stated above, is caused to react with at least one compound of the general formula VII,
in which    R1, R2, R3, R4, R5, R6, and R7, have the meanings stated above, in a reaction medium, optionally in the presence of at least one suitable coupling agent, optionally in the presence of at least one base,    or with at least one compound of the general formula VIII,
in which    R1, R2, R3, R4, R5, R6, and R7 have the meanings stated above and LG stands for a leaving group, preferably for a chlorine radical or bromine atom, in a reaction medium, optionally in the presence of at least one base,    to form at least one compound of the general formula Im,
in whichT, U, V, W, R1, R2, R3, R4, R5, R6, R7, and R8 have the meanings stated above, and this is optionally purified and/or isolated.
The reaction of compounds of the above general formulas V or X with carboxylic acids of the above general formula VII to form compounds of the above general formulas I or Im is carried out preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1,2)-dichloroethane, dimethylformamide, dichloromethane and appropriate mixtures thereof, optionally in the presence of at least one coupling agent, preferably selected from the group consisting of 1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI), diisoproylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), N-[(dimethylamino)-1H-1,2,3-triazolo[4.5-b]pyridino-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), O-(benzotriazol-1-yl)-N,N,N′N-tetramethyluronium hexafluorophosphate (HBTU), O(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxybenzotriazole (HOBT), and 1-hydroxy-7-azabenzotriazole (HOAt), optionally in the presence of at least one organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine, and diisopropylethylamine, preferably at temperatures ranging from −70° C. to 100° C. Alternatively, the reaction of compounds of the above general formulas V or X with carboxylic derivatives of the above general formula VIII, in which LG stands for a leaving group, preferably for a chlorine radical or bromine atom, to form compounds of the above general formulas Im is carried out in a reaction medium preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and appropriate mixtures thereof, optionally in the presence of an organic or inorganic base, preferably selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine, and diisopropylamine, at temperatures ranging from −70° C. to 100° C.
The compounds of the above formulas II, III, IV, V, VI, VII, X and VIII are all commercially available and can be obtained by methods known to the person skilled in the art.
The synthesis of compounds of the general formula VII is described in the paper “4-(Methylsulfonylamino)phenyl analogues as vanilloid antagonist showing excellent analgesic activity and the pharmaceutical compositions comprising the same” by J. W. Lee et al. [WO 2005/003084-A1].
The appropriate sections of this reference are included herein by reference and are to be regarded as part of the disclosure.
The conversions described above can each be carried out under usual conditions well-known to the person skilled in the art, for example, in respect of pressure or order of addition of the components. Optionally, the optimal procedure under the respective conditions can be determined by the person skilled in the art using simple preliminary tests. The intermediates and end products obtained by the aforementioned reactions can in each case be isolated and/or purified by conventional methods known to the person skilled in the art, if desired and/or necessary. Suitable clean-up techniques are, for example, extraction processes and chromatographic processes such as column chromatography or preparative chromatography. All of the process steps described above and the purification and/or isolation of intermediate or end products can be carried out partially or completely under a blanket of inert gas, preferably under a blanket of nitrogen. The substituted compounds of the invention of the aforementioned general formulas I, Ia, Ib and Ic, designated below simply as compounds of the general formula I, and corresponding stereoisomers can be isolated either in the form of the free bases thereof, the free acids thereof or in the form of corresponding salts, particularly physiologically acceptable salts.
The free bases of the respective substituted compounds of the invention of the aforementioned general formula I and corresponding stereoisomers can, for example by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, or aspartic acid, be converted to the corresponding salts, preferably physiologically acceptable salts. The free bases of the respective substituted compounds of the aforementioned general formula I and corresponding stereoisomers can be likewise caused to react with the free acid or a salt of a sugar substitute, such as saccharin, cyclamate, or acesulfam, to form the corresponding physiologically acceptable salts. Similarly, the free acids of the substituted compounds of the aforementioned general formula I and corresponding stereoisomers can be caused to react with of a suitable base to form the corresponding physiologically acceptable salts. Mention may be made, for example, of the alkali-metal salts, alkaline earth metal salts, or ammonium salts [NHxR4-x]+ in which x is equal to 0, 1, 2, 3, or 4, and R stands for a linear or branched C1-4 alkyl radical.
The substituted compounds of the invention designated by the aforementioned general formula I and corresponding stereoisomers can optionally, like the corresponding acids, the corresponding bases or salts of these compounds, be obtained in the form of the solvates thereof, preferably in the form of the hydrates thereof, by conventional methods known to the person skilled in the art.
If the substituted compounds of the invention designated by the aforementioned general formula I are obtained, following production thereof, in the form of a mixture of the stereoisomers thereof, preferably in the form of the racemates thereof or other mixtures of the various enantiomers and/or diastereoisomers thereof, these compounds can be separated and, if desired, isolated by methods known to the person skilled in the art.
Examples of suitable isolation methods include chromatographic separation methods, particularly liquid-chromatographic methods carried out under standard pressure or at elevated pressure, preferably MPLC and HPLC methods, and also methods of fractional crystallization. In particular, individual enantiomers can be separated from each other, e.g., diastereoisomeric salts formed by means of HPLC on chiral stationary phase or by means of crystallization with chiral acids, say, (+)-tartaric acid, (−)-tartaric acid, or (+)-10-camphorsulfonic acid.
The substituted compounds of the invention designated by the aforementioned general formula I and corresponding stereoisomers and in each case the corresponding acids, bases, salts, and solvates are toxicologically safe and are therefore suitable for use as pharmaceutically active substances in medicinal drugs.
The invention therefore further relates to a medicinal drug containing at least one compound of the invention of the above general formula I, each optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers thereof, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or each in the form of a corresponding salt, or each in the form of a corresponding solvate, and optionally one or more pharmaceutically compatible adjuvants.
These medicinal drugs of the inventions are particularly suitable for vanilloid receptor 1-(VR1/TRPV1) regulation, preferably vanilloid receptor 1-(VR1/TRPV1) inhibition and/or vanilloid receptor 1-(VR1/TRPV1) stimulation.
In another preferred embodiment, the medicinal drugs of the invention are suitable for prophylaxis and/or treatment of disorders or diseases that are at least partially mediated by vanilloid receptors 1.
Preferably, the medicinal drug of the invention is suitable for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; arthralgia; hyperalgesia; allodynia; causalgia; migraine; states of depression; nervous disorders; neurotraumas; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; epilepsy; respiratory tract diseases, preferably selected from the group consisting of asthma, bronchitis, and pneumonia; coughing; urinary incontinence; an overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; colitis syndrome; apoplectic strokes; eye irritations; cutaneous irritations; neurotic skin conditions; allergic skin diseases; psiorasis; vitiligo; Herpes simplex; inflammations, preferably inflammation of the intestine, the eyes, the bladder, the skin, or the nasal mucosa; diarrhea; pruritus; osteoporosis; arthritis; osteo-arthritis; rheumatic disorders; food intake disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia, and obesity; medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceuticals, particularly to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction; for diuresis; for antinatriuresis; for affection of the cardiovascular system; for vigilance enhancement; for treatment of wounds and/or burning; for treatment of severed nerves; for libido enhancement; for modulation of movement activity; for anxiolysis; for local anesthesia and/or for inhibition of undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension, and bronchial constriction, as is caused by administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil, and capsavanil.
The medicinal drug of the invention is more preferably suitable for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain; arthralgia; migraine; states of depression; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; inflammation, preferably inflammation of the intestine, the eyes, the bladder, the skin or the nasal mucosa; urinary incontinence; an overactive bladder (OAB); medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceuticals, preferably tolerance development to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction.
The medicinal drug of the invention is most preferably suitable for treatment and/or prophylaxis of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain, and/or urinary incontinence.
The invention further relates to the use of at least one compound of the invention and optionally one or more pharmaceutically compatible adjuvants for the production of a medicinal drug for vanilloid receptor 1-(VR1/TRPV1) regulation, preferably vanilloid receptor 1-(VR1/TRPV1) inhibition and/or vanilloid receptor 1-(VR1/TRPV1) stimulation.
Preference is given to the use of at least one substituted compound of the invention and optionally one or more pharmaceutically compatible adjuvants for the production of a medicinal drug for the prophylaxis and/or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1.
Particular preference is given to the use of at least one compound of the invention and optionally one or more pharmaceutically compatible adjuvants for the production of a medicinal drug for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain, and arthralgia. Particular preference is given to the use at least one compound of the invention and optionally one or more pharmaceutically compatible adjuvants for the production of a medicinal drug for treatment and/or prophylaxis of one or more disorders selected from the group consisting of hyperalgesia; allodynia; causalgia; migraine; states of depression; nervous disorders; neurotraumas; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; epilepsy; respiratory tract diseases, preferably selected from the group consisting of asthma, bronchitis, and pneumonia; coughing; urinary incontinence; an overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; colitis syndrome; apoplectic strokes; eye irritations; cutaneous irritations; neurotic skin conditions; allergic skin diseases; psiorasis; vitiligo; Herpes simplex; inflammation, preferably inflammation of the intestine, the eyes, the bladder, the skin, or the nasal mucosa; diarrhea; pruritus; osteoporosis; arthritis; osteo-arthritis; rheumatic disorders; food intake disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia, and obesity; medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceuticals, preferably to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction; for diuresis; for antinatriuresis; for affection of the cardiovascular system; for vigilance enhancement; for treatment of wounds and/or burning; for treatment of severed nerves; for libido enhancement; for modulation of movement activity; for anxiolysis; for local anesthesia and/or for inhibition of undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension, and bronchial constriction, as caused by administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil, and capsavanil.
Very high preference is given to the use of at least one substituted compound of the invention and optionally one or more pharmaceutically compatible adjuvants for the production of a medicinal drug for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain; is arthralgia; migraine; states of depression; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; inflammation, preferably inflammation of the intestine, the eyes, the bladder, the skin, or the nasal mucosa; urinary incontinence; an overactive bladder (OAB); medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceuticals, preferably tolerance development to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction.
Even more preference is given to the use of at least one substituted compound of the invention and optionally one or more pharmaceutically compatible adjuvants for the production of a medicinal drug for treatment and/or prophylaxis of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain, and/or urinary incontinence.
The medicinal drug of the invention is suitable for administration to adults and children including infants and babies.
The medicinal drug of the invention can exist as a liquid, semisolid, or solid pharmaceutical dosage form, for example, in the form of injection fluids, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, or aerosols, or in a multiparticular form, for example, in the form of pellets or granules, optionally compressed to tablets, filled into in capsules, or suspended in a liquid, and can be administered as such.
In addition to at least one substituted compound of the above general formula I, optionally in the form of a pure stereoisomer thereof, particularly an enantiomer or diastereoisomer, the racemate thereof or in the form of mixtures of the stereoisomers, particularly the enantiomers or diastereoisomers, in an arbitrary mixing ratio, or optionally in the form of a corresponding salt or each in the form of a corresponding solvate, the medicinal drug of the invention usually contains further physiologically acceptable pharmaceutical adjuvants, which, for example, can be selected from the group consisting of vehicles, fillers, solvents, diluents, surfactants, dyes, preservatives, blasting agents, slip agents, lubricants, flavors, and binding agents.
The selection of the physiologically acceptable adjuvants and the amount thereof to be used depends on whether the medicinal drug is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, e.g., to infected parts of the skin, the mucous membrane, or the eyes. Preparations suitable for oral administration are preferably in the form of tablets, dragees, capsules, granules, pellets, drops, juices, and syrups, and preparations suitable for parenteral, topical and inhalative administration are solutions, suspensions, readily reconstitutable dry preparations, and sprays. The substituted compounds of the invention used in the medicinal drug of the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration enhancing agents, are suitable percutane administration forms. Formulations for oral or percutane application may be such as to effect delayed release of the respective substituted compound of the invention. The production of the medicinal drug of the invention is effected by conventional means, devices, methods, and processes, as are known in the prior art, such as are described, for example, in “Remington's Pharmaceutical Sciences”, Editor A. R. Gennaro, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, particularly in Section 8, Chapters 76 to 93. The corresponding description is incorporated herein by reference and is to be regarded as part of the disclosure. The amount of the respective substituted compounds of the invention of the above general formula I to be administered to the patients can vary and is dependent, for example, on the weight or age of the patient and also on the method of administration, the indication, and the severity of the disorder. Usually from 0.001 to 100 mg/kg, preferably from 0.05 to 75 mg/kg and more preferably from 0.05 to 50 mg/kg, of body weight of the patient of at least one such compound of the invention are administered.
Pharmacological Methods:
I. Functional Investigation on the Vanilloid Receptor 1 (VR1/TRPV1 Receptor)
The agonistic or antagonistic action of the substances to be investigated on the vanilloid receptor 1 (VR1/TRPV1) of the species rat can be determined using the following assay. According to this assay, the Ca2+ influx through the receptor channel is quantified with the aid of a Ca2+-sensitive dye (Type Fluo-4, Molecular Probes Europe BV, Leiden Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
Method:
Complete medium: 50 mL of HAMS F12 Nutrient Mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany) with
10% by volume of FCS (fetal calf serum, Gibco Invitrogen GmbH, Karlsruhe, Germany, heat-inactivated);
2 mM of L-glutamine (Sigma, Munich, Germany);
1% by weight of AA solution (antibiotics/antimycotics solution, PAA, Pasching, Austria)
and 25 ng/mL of Medium NGF (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany) Cell culture plate: Poly-D-lysine-coated, black 96-well plates with a clear bottom (96-well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Karlsruhe, Germany) by diluting laminin to a concentration of 100 μg/mL with PBS (Ca—Mg-free PBS, Gibco Invitrogen GmbH, Karlsruhe, Germany). Aliquots having a concentration of 100 μg/mL of laminin are taken and stored at −20° C. The aliquots are diluted with PBS in the ratio 1:10 to 10 μg/mL of laminin and in each case 50 μL of the solution is pipeted into a well of the cell culture plate. The cell culture plates are incubated at 37° C. for at least two hours, the supernatant solution is aspirated and the wells are in each case washed twice with PBS. The coated cell culture plates are stored with supernatant PBS and this is removed only directly before the addition of the cells.
Preparation of the Cells:
The vertebral column is removed from decapitated rats and this is laid directly in a cold, i.e. ice bath-surrounded, HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) and 1% by volume of an AA solution (antibiotics/antimycotics solution, PAA, Pasching, Austria) is added. The vertebral column is cut in two, longitudinally, and the vertebral canal is removed together with fascias. Subsequently, the dorsal root ganglia (DRGs) are removed and in turn stored in cold HBSS buffer to which 1% by volume of an AA solution has been added. The DRGs completely freed from blood residues and spinal nerves are in each case transferred to 500 μL of cold collagenase Type 2 (PAA, Pasching, Austria) and incubated at 37° C. for 35 minutes. After the addition of 2.5% by volume of trypsin (PAA, Pasching, Austria), the preparation is incubated at 37° C. for a further 10 minutes. On completion of incubation, the enzyme solution is carefully pipeted off and 500 μL of complete medium are added to the DRGs in each case. The DRGs are in each case repeatedly suspended, drawn through No. 1, No. 12, and No. 16 needles by means of a syringe and transferred to 50 mL Falcon tubes and these are filled to 15 mL with complete medium. The contents of each Falcon tube are in each case filtered through a 70 μm Falcon filter insert and centrifuged at 1200 rpm and RT for 10 minutes. The resulting pellet is in each case taken up in 250 μL of complete medium and the cell count is determined.
The number of cells in the suspension is adjusted to 3×105 per mL and in each case 150 μL of this suspension are added to a well of the cell culture plates coated as described above. The plates are allowed to stand at 37° C., 5% by volume of CO2 and 95% relative humidity for two to three days in an incubator.
Subsequently, the cells are loaded with 2 μM of Fluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) at 37° C. for 30 min, washed 3 times with HBSS buffer and, after a further incubation of 15 minutes at RT, employed in the FLIPR assay for Ca2+ measurement. The Ca2+-dependent fluorescence is measured before and after addition of substances (λex=488 nm, λem=540 nm). Quantification is carried out by measuring the highest fluorescence intensity (FC, fluorescence counts) over time.
FLIPR assay:
The FLIPR protocol consists of two substance additions. Initially, the compounds to be tested (10 μM) are pipeted onto the cells and the Ca2+ influx is compared with the control (capsaicin 10 μM). Information is gained therefrom in percentage activation relative to the Ca2+ signal after addition of 10 μM of capsaicin (CP). After incubation for 5 minutes, 100 nM of capsaicin are applied and the influx of Ca2+ is likewise determined.
Desensitizing agonists and antagonists lead to suppression of the Ca2+ influx. The percentage inhibition is calculated in comparison with the maximum inhibition achieved with 10 μM of capsaicin. Conversion using the Cheng Prusoff equation gave Ki values for the test substances (Cheng, Prusoff; Bioch. Pharmacol. 22, 3099-3108, 1973).
II. Functional Investigations on the Vanilloid Receptor (VR1)
The agonistic or antagonistic action of the substances to be examined on the vanilloid receptor (VR1) can alternatively be determined by the following assay. According to this assay the Ca2+ influx through the canal is quantified with the aid of a Ca2+-sensitive dye (type Fluo-4, Molecular Probes, Europe BV, Leiden, Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
Method:
Chinese hamster ovary cells (CHO—K1 cells, European Collection of Cell Cultures (ECACC) UK) are stably transfected with the VR1 gene. For carrying out functional investigations, these cells are plated on poly-D-lysine-coated, black 96-well plates with a clear bottom (BD Biosciences, Heidelberg, Germany) in a density of 25,000 cells/well. The cells are incubated overnight at 37° C. and 5% CO2 in a culture medium (Nutrient Mixture ‘am’s F12, 10% by volume of FCS (fetal calf serum), 18 μg/mL of L-proline). On the following day the cells are incubated with Fluo-4 (Fluo-4 2 μM, Pluronic F127 0.01 by volume, Molecular Probes in HBSS (Hank's buffered saline solution), Gibco Invitrogen GmbH, Karlsruhe, Germany) for 30 minutes at 37° C. The plates are then washed 3 times with HBSS buffer and, after another incubation over a period of 15 minutes at RT, are used in the FLIPR for Ca2+ measurement. The Ca2+-dependent fluorescence is measured prior to and following the addition of the substances being examined (wavelength λex=488 nm, λem=540 nm). Quantification is carried out by measuring the highest fluorescence intensity (PC, fluorescence counts) over time.
FLIPR Assay:
The FLIPR protocol consists of two substance additions. First of all, the substances to be tested (10 μM) are pipeted onto the cells and the Ca2+ influx is compared with the control (capsaicin 10 μM) (percentage activation based on the Ca2+ signal following addition of 10 μM of capsaicin). Following incubation over a period of 5 minutes 100 nM of capsaicin are applied and the influx of Ca2+ is likewise determined.
Desensitizing agonists and antagonists lead to a suppression of the Ca2+ influx. The percentage inhibition compared with the maximum inhibition achieved with 10 μM of capsaicin is calculated.
Based on the percentage displacement effected by different concentrations of the compounds of the general formula Ito be tested, IC50 inhibition concentrations that cause 50 percent displacement of capsaicin are calculated. Conversion using the Cheng Prusoff equation gave Ki values for the test substances (Cheng, Prusoff; Bioch. Pharmacol. 22, 3099-3108, 1973).
III. Formalin Test on Mice
The investigation for the determination of the antinociceptive action of the compounds of the invention is carried out in the formalin test on male mice (NMRI, of 20 to 30 g body weight, Iffa, Credo, Belgium).
In the formalin test, the first (early) phase (0 to 15 minutes after the formalin injection) and the second (late) phase (15 to 60 minutes after the formalin injection) are distinguished according to D. Dubuisson et al., Pain 1977, 4, 161-174. The early phase, as a direct reaction to the formalin injection, is a model of acute pain, whereas the late phase is regarded as a model of persistent (chronic) pain (T. J. Coderre et al., Pain 1993, 52, 259-285). The appropriate literature references are incorporated herein by reference and are to be regarded as part of the disclosure.
The compounds of the invention are examined in the second phase of the formalin test, in order to obtain information concerning a substance's action on chronic/inflammatory pain.
The point in time of administration of the compounds of the invention before the formalin injection is selected according to the method of administration of the compounds of the invention. Intravenous administration of 10 mg/kg of body weight of the test substance is carried out 5 minutes before the formalin injection. This is carried out by a single subcutaneous formalin injection (20 μL, 1% strength aqueous solution) into the dorsal side of the right hind paw so that in the case of free-moving experimental animals a nociceptive reaction is induced which is manifested by marked licking and biting of the relevant paw.
The nociceptive behavior is then continuously registered during an investigation period of three minutes in the second (late) phase of the formalin test (21 to 24 minutes after the formalin injection) by observation of the animals. Quantification of the pain behavior is carried out by summating the seconds during which the animals show licking and biting of the relevant paw during the investigation period.
In each case, comparison is carried out with control animals, which receive, instead of the compounds of the invention, a vehicle (0.9% strength aqueous sodium chloride solution) prior to formalin administration. Based on the quantification of the pain behavior, the substance's action in the formalin test is determined as the degree of change compared with the corresponding control.
Following injection of the substances having an antinociceptive action in the formalin test, the aforementioned behavioral patterns of the animals, i.e. licking and biting, decrease or cease.
IV. Test for Analgesic Effectiveness in the Writhing Test
Investigation of the compounds of the general formula I of the invention for analgetic effectiveness was carried out based on phenylquinone-induced writhing in mice, modified after I. C. Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240. The corresponding literature reference is incorporated herein by reference and is to be regarded as part of the disclosure.
For this purpose, male NMRI mice having a weight of from 25 to 30 g were used. Groups of 10 animals per dose of the test compound received by intraperitoneal administration, 10 minutes after intravenous administration of the compound under test, 0.3 mL/mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, marketed by Sigma, Deisenhofen, Germany and produced by adding to the solution 5% by weight of ethanol and storing it in a water bath at 45° C.). The animals were placed individually in observation cages. With the aid of a pushbutton counter, the number of pain-induced stretching movements (so-called writhing reactions—straightening of the body with stretching of the rear extremities) was counted over a period of from 5 to 20 minutes following the administration of the phenylquinone. The control was provided by animals receiving only physiological saline. All of the compounds were tested using the standard dosage of 10 mg/kg.
V. Hypothermia Assay in Mice
Description of the Method:
The hypothermia assay was carried out on male NMRI mice (weight 25-35 gram, Zuechter IFFA CREDO, Brussels, Belgium). The animals were kept under standardized conditions: light/dark rhythm (from 6:00 to 18:00 hours light phase; from 18:00 to 6:00 hours dark phase), RT 19-22° C., relative air humidity 35-70%, 15 air changes per hour, air movement <0.2 m/sec. The animals received standard feed (ssniff R/M−Haltung, ssniff Spezialdiaeten GmbH, Soest, Germany) and tap water.
Water and feed were withdrawn during the experiment. All animals were used only once during the experiment. The animals had an acclimatization period of at least 5 days.
Acute administration of capsaicin (VR-1 agonist) leads to a drop in the core temperature of the body in rats and mice due to stimulation of heat sensors. Only specifically effective VR-1 receptor antagonists can antagonize the capsaicin-induced hypothermia. By contrast, hypothermia induced by morphine is not antagonized by VR-1 antagonists. This model is therefore suitable for identifying substances with VR-1 antagonistic properties via their effect on body temperature.
Measurement of the core temperature is carried out using a digital thermometer (Thermalert TH-5, physitemp, Clifton N.J., USA). The sensing element is inserted into the rectum of the animals.
To give an individual basic value for each animal, the body temperature is measured twice at an interval of approximately half an hour. One group of animals (n=6 to 10) then receives an intraperitoneal (i.p.) application of capsaicin 3 mg/kg and vehicle (control group). Another group of animals receives the substance to be tested (i.v. or p.o.) and additionally capsaicin (3 mg/kg) i.p. The administration of the test substance is carried out i.v. 10 min, or p.o 15 minutes, prior to capsaicin. The body temperature is then measured 7.5/15 and 30 min following capsaicin (i.v.+.p.) or 15/30/60/90/120 min (p.o.+i.p.) following capsaicin. In addition, one group of animals is treated with the test substance only and one group with vehicle only. The evaluation or representation of the measured values as mean+/−SEM of the absolute values is presented as a graphical representation. The antagonistic action is calculated as the percentage reduction of the capsaicin-induced hypothermia.
VI. Neuropathic Pain in Mice
The investigation on effectiveness on neuropathic pain was examined using the Bennett Model (chronic constriction injury; Bennett and Xie, 1988, Pain 33:87-107). Three loose ligatures are tied around the right ischiadic nerve of Ketavet/Rompun-anesthetized NMRI mice weighing 16-18 g. The animals develop hypersensitivity of the nervate paw caused by the damaged nerve, which hypersensitivity is quantified, following a recovery phase of one week, over a period of approximately three weeks by means of a cold metal plate (temperature 4° C.) (cold allodynia). The animals are observed on this plate over a period of 2 min, and the withdrawal reactions of the damaged paw are counted. Based on the pre-value prior to administration of substance, the substance's action over a certain period of time is determined at various points in time (e.g., 15, 30, 45, or 60 min following administration) and the resultant area under the curve (AUC) and/or the inhibition of cold allodynia at the individual measuring points was/were expressed as percentage action relative to the vehicle control (AUC) or to the starting value (individual measuring points). The group size is n=10, the significance of an anti-allodynic action (*=p<0.05) is determined with the aid of an analysis of variance with repeated measures and Bonferroni post hoc analysis.
The invention is described below with reference to some examples. These explanations are by way of example only and do not restrict the general inventive concept.